| Summary: | The adult vertebrate forebrain is responsible for a diverse set of behaviors, and as such exhibits complex anatomy. This complexity is generated during embryogenesis whereby a specific spatiotemporal sequence of transcriptional and signaling programs promotes specification of different cell types based on the location and developmental potential of progenitors. Six3 is one such transcription factor that exerts multiple functions in the development of anterior neural tissue of vertebrate embryos. Whereas complete loss of Six3 function in the mouse results in failure of forebrain formation, its hypomorphic mutations in human and mouse can promote holoprosencephaly, a forebrain malformation resulting, at least in part, from abnormal telencephalon development. However, Six3s roles in telencephalon patterning and differentiation are not well understood. The zebrafish genome contains three Six3-related genes facilitating analysis of different partial loss-of-function combinations. I analyzed zebrafish embryos deficient in two of three Six3-related genes, six3b and six7, representing a partial loss of Six3 function. Telencephalon forms in six3b;six7-deficient embryos, however ventral telencephalic domains are reduced and dorsal domains are expanded. Decreased cell proliferation or excess apoptosis cannot account for the ventral deficiency. Instead, six3b and six7 are required during early segmentation for specification of ventral progenitors, similar to the role of Hedgehog signaling in telencephalon development. Unlike in mice, Hedgehog signaling is not disrupted in embryos with reduced Six3 function. Furthermore, six3b overexpression is sufficient to compensate for loss of Hedgehog signaling in isl1- but not nkx2.1b-positive cells, suggesting a novel Hedgehog-independent role for Six3 in telencephalon patterning. Additional investigations into the interactions between Six3 and known telencepnalon patterning genes showed that Six3 promotes ventral telencephalic fates through transient regulation of foxg1a expression and repression of Wnt/β-catenin pathway. As Six3-related genes are expressed broadly in prechordal mesoderm and anterior neuroectoderm, transgenic zebrafish were generated to identify the spatial requirement for Six3 function in telencephalon patterning. My studies help define the cellular mechanisms of Six3-mediated dorsoventral patterning in telencephalon and present a novel genetic mechanism by which Six3 regulates this process.
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